Investigating the role of maternal-fetal crosstalk on neonatal immunity in COVID-19 infection or vaccination in pregnancy

ABSTRACT Passive transfer of immunoglobulins (IgG) against SARS-CoV-2 occurs from the mother to fetus by transplacental transfer and may protect the neonate against infection or cause disease. Recent studies have shown maternal SARS-CoV-2 infection leads to the dysregulation of infant immune responses in cord blood including altered T cell related cytokines and perturbations of immune cell subsets. It has not been yet shown if this immune priming is SARS-CoV-2 antigen-specific or if it is secondary to non-specific maternal or placental inflammation. Additionally, recent evidence has shown waning immunity after vaccination and further work is needed to understand protective immunogenic responses to SARS-CoV-2 epitopes to optimize future vaccination strategies in pregnancy, to benefit both mother and infant. We hypothesize that maternal SARS- CoV-2 infection actively primes fetal immune responses in utero through 1) the transfer of immune complexes with immunostimulatory activity, and 2) the passive transfer of both protective and autoreactive antibodies to the fetus. Further, we hypothesize that differential placental tissue responses correlate with differences in maternal- fetal crosstalk. In this application, we leverage valuable samples from two prospective cohorts of COVID-19 infection and vaccination in pregnancy to address the following specific aims: 1) Investigate the fetal T cell immunostimulatory potential of SARS-CoV-2 Ags transferred to the fetus in immune complexes through a novel mass spectrometry-based approach; 2) Map the antibody repertoire profiles of Abs generated after SARS-CoV- 2 infection vs vaccination to determine the breadth of maternal-fetal transfer of protective vs autoreactive immune responses using PhIP-Seq technology; and 3) Identify differential transcriptomic and proteomic responses to SARS-CoV-2 infection at the maternal-fetal interface that mediate differences in immune complex transfer through the application of laser microdissection on patient biopsies. These results have immediate relevance to understanding novel mechanisms of maternal-fetal immune crosstalk after viral infection. Our data will aid vaccination strategies to protect both the mother and baby against COVID-19 and may significantly advance in our understanding of maternal-fetal immune interplay in perinatal infections.